Roles of methyltransferases in the development of resistance to thiol-based histone deacetylase inhibitors

Authors

• OD Gbadegesin
• RW Robey
• MM Gottesman

Abstract

Histone deacetylases (HDACs) are enzymes that are involved in regulating levels of histone acetylation affecting chromosome structure and gene expression. Some are FDA-approved for treatment of cancer, but resistance develops in the clinic. This work aims to investigate methyltransferases as a mechanism of resistance to ST7612AA1, an oral thiol-based pan-HDAC inhibitor that has shown promise in preclinical studies as an anticancer drug. A previous study showed that the putative methyltransferase-like protein, METTL7A, conferred resistance to romidepsin, a thiol-based HDAC inhibitor, by methylating its zinc-binding thiol group. To determine whether METTL7A can inactivate other thiol-based HDAC inhibitors, we treated a romidepsin-resistant MCF-7 breast cancer cell line which overexpressed METTL7A with ST7612AA1. The romidepsin-resistant MCF-7 breast cancer cell line exhibited cross-resistance to ST7612AA1. Furthermore, we selected MCF-7 human breast cancer cells using ST7612AA1. At 10 µM and 50 µM concentrations of ST7612AA1, the resulting resistant cell lines expressed METTL7A and were resistant to ST7612AA1 and other thiol-based HDAC inhibitors. Further characterization of the ST7612AA1-resistant MCF-7 cell lines will provide more insights into the mechanism by which methyltransferases confer resistance to HDAC inhibitors. The study will provide more information on METTL7A as a novel mechanism of resistance to HDAC inhibitors and a potential target for cancer treatment.

Scientific Focus Area: Cancer Biology

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